Studies are in progress towards the design and synthesis of new phencyclidine (PCP)-like compounds as neuroprotective agents and as anticonvulsants. PCP-like compounds have been reported to exert a protective effect against neuronal degeneration in ischemia models; evidence suggests they act as antagonists against the depolarizing action of N-methyl-D-aspartate (NMDA) in animal brain. PCP binding sites exist in excitatory amino acid controlled ion channels regulated by glutamate receptors of the NMDA type, as well as in the dopamine uptake complex. Our demonstration of the existence of a high-affinity PCP binding site associated with the dopamine reuptake carrier raises the possibility that the therapeutic and psychotomimetic effects of PCP in humans are separable and mediated via different binding sites. We also synthesized two MK-801 isothiocyanates as potential affinity ligands. One of these has proven to be more potent and selective in its interaction with the PCP binding sites than our former affinity ligands; it interacts minimally with the dopaminergic reuptake system. Sigma receptors are non-dopaminergic, non-opioid receptors which bind antipsychotic drugs and have been implicated in neural regulation of motor behavior and modulation of transmitter release upon electrical stimulation of smooth muscle preparations. We have identified a novel class of high- affinity sigma receptor ligands, the enantiomeric N-substituted cis-N-[2- (3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylamines. The most potent, site selective, sigma ligand found in this group was the 1R,2S-(-)- unsubstituted derivative (Ki=0-49 nM). Related compounds constitute a new class of superpotent sigma ligands. Optically pure [3H](+)-cis-N-(2-(4- azidophenyl)ethyl)-2'-hydroxy-2,6-dimethyl-6,7-benzomorphan was synthesized and characterized as a high-affinity and highly selective benzomorphan- based photoaffinity label for sigma receptors. Cannabinoid receptors were characterized and localized through an in vivo autoadiographic study in rat brain. Neuronal localization of these receptors occurred in the basal ganglia of the rat. The function of these receptors in the brain is being sought.